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https://doi.org/10.1057/s41599-020-0478-4 OPEN Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures ✉ Charlotte Brives 1 & Jessica Pourraz2

ABSTRACT Phage therapy, the use of bacteriophage viruses to treat bacterial infections, has existed for more than a hundred years. However, the practice is struggling to develop, despite growing support over the past 15 years from researchers and doctors, who see it as a

1234567890():,; promising therapy in the context of the rise of antimicrobial resistance (AMR). While the reasons for these developmental difficulties are complex, in this article we wish to address the effects of pharmaceutical regulations on phage therapy. By showing how phages are assimilated to an umpteenth antibiotic in legal texts, but also in certain medical practices, this article proposes to analyze the consequences of such regulatory categorization both for their production and the logistics of administration of proof of their efficacy in randomized con- trolled trials (RCTs), as well as the underlying concepts of infection and treatment. This paper follows Chandler’s work on the concept of antibiotics as infrastructure and its inversion presented by antimicrobial resistance. Phages as living, dynamic, evolving, and specific entities, do not lend themselves easily to current categories, norms, and development models. In this sense, they act as disruptors, revealing the limitations imposed by the existing infrastructure. More precisely here, and to continue Chandler’s initial thought process, this paper aims to show that antibiotics also form a kind of epistemological infrastructure, which acts as a powerful inhibitor to the development of phage therapy. In this sense antibiotics prevent the development of solutions to the problem they contribute to create. But the difficulties phage therapy faces, as highlighted in this article, can be interpreted as entry points for thinking of another medicine and imagining other possible futures. This analysis is based on a 3-year fieldwork study (2016–2019) in Europe (France, Belgium, and Switzerland), during which we conducted semi-directed interviews with various phage therapy stake- holders (physicians, researchers, pharmacists, regulators, patients, and patient associations), participatory observation in labs and observations during symposia and workshops on phages and phage therapy.

✉ 1 CNRS, Bordeaux, France. 2 Faculté de Sociologie, Université de Bordeaux, Bordeaux, France. email: [email protected]

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Introduction hage therapy, the use of bacteriophage viruses to treat the materiality of phages, evolving entities, imposes constraints bacterial infections, has existed for more than a hundred on both the respect of production norms imposed by regulations P ’ years (D Hérelle, 1931). However, the practice is struggling and the dominant model of drug development based on to develop, despite growing support over the past 15 years from scalability. researchers and doctors, who see it as a promising therapy in the After a brief review of the history of phage therapy and the context of the rise of antimicrobial resistance (AMR). While the mode of action of phages, we will describe the regulations in force reasons for these developmental difficulties are complex, in this in Europe, which classify bacteriophage viruses as medicinal article we wish to address the effects of pharmaceutical regula- products and their use, particularly in the French context. tions on phage therapy. For this we have adopted a theoretical By showing how phages are assimilated to an umpteenth approach from science and technology studies (STS) and philo- antibiotic in legal texts, but also in certain medical practices, we sophy of science. More precisely, we use the material-semiotic will analyze the consequences of such regulatory categorization method of the actor-network theory, and the principle of gen- for their production and for the administration of proof of their eralized symmetry that places humans and non-humans on the efficacy in randomized controlled trials (RCTs), as well as the same analytical plane (Callon, 1986; Latour, 2004). Our postulate underlying concepts of infection and treatment. is that we cannot understand the difficulties of phage therapy We will conclude with how some of the difficulties facing without taking into account both the socio-political context and phage therapy highlighted in this article can be interpreted as the very materiality of phages, their characteristics and entry points for imagining other possible futures. specificities. This analysis is informed by 3 years of fieldwork (2016–2019). Indeed, efforts to make phage therapy a viable and widely shared As one of us is a member of various scientific networks on phage practice must be analyzed within the framework of the AMR research and applications, and has trained in Biological Sciences, problem and the solutions proposed to deal with it (Podolsky, Anthropology of Science and Biomedical Sciences, she was able to 2018). More broadly, while the need to reduce antibiotic use by conduct participatory observations in laboratory contexts. We modulating individual behaviors is often highlighted (Broom et al., participated as observers in 10 symposia and workshops on 2015), it is the systemic and institutionalized dimension of anti- bacteriophages and phage therapy, during which we conducted biotics and their use that must be taken into account to understand intensive informal discussions with participants. We also con- how a new practice may or may not emerge. ducted 30 semi-directive and/or open interviews with scientists, The development of antibiotics, but above all of their modes of physicians, pharmacists, patients, start-up actors and regulatory production (Bud, 2009) and of mass-consumption, in both agency officers.1 As anthropologists, we are also part of a Ran- human and animal health (Hinchliffe et al., 2018; Kirchhelle, domized Controlled Trial, the aim of which is to assess the added 2018; Fortané, 2019), have had a profound and lasting impact on value of phages for bone infections. both human societies and bacteria, thus reminding us that the These different implications within the phage therapy field latter are not inert matter, but living organisms that act and react meant one of us could participate to a specialized committee on to their environment (Landecker, 2016). phage therapy at the French National Agency for the Safety of In a 2018 article, Chandler proposes to mobilize the notion of Medicines and Health Products (ANSM). From a strong inter- “infrastructure” as developed by Bowker and Star (1999), among disciplinary perspective, we also presented our work in work- others, as an analytical and programmatic framework to under- shops on phage therapy and in a Jacques Monod conference on stand the question of AMR: “Such infrastructure comprises viral evolution, generating added conversations and data about materials, information, ordering. For example, the availability and actors’ perspectives on the development of phage therapy. usability of research instruments and subjects shapes what science is constructed; the supply chain, techniques, and subject handling methods are invented alongside biology’s conceptual frame” A brief history of phage therapy (Chandler, 2018, p. 9). Chandler shows how “the present Not all viruses are pathogenic to humans. In fact, there is a awareness of antimicrobial resistance appears to have produced category of virus, bacteriophage viruses (or phages), which are an inversion whereby antimicrobials, and their attendant rela- hosted by bacteria. The human population will soon reach eight tions and processes, have come to the fore. This enables analyses billion, but the number of phages present in ecosystems is esti- of the possibilities, conventions, and constraints that have mated at more than 1031, making them the most represented hitherto been taken for granted as common sense, and the biological entity on Earth. These creatures, made up of protein or potential for reshaping these into the future” (Chandler, 2018). proteolipidic capsides containing fragments of nucleic acids (most This inversion of the infrastructure presented by AMR, and the often DNA, but also RNA), are present wherever bacteria can opportunity it offers to think of another medicine, seems to us to be be found. particularly highlighted by the case of phage therapy. Phages, living Humans have come to know and recognize them since the and dynamic, evolving and specific entities, do not lend themselves beginning of the 20th century. First mentioned in 1915 by Fre- easily to current categories, norms and development models. In this derick Twort (1915), they owe their therapeutic applications to sense, they are disruptors, revealing the limitations imposed by the Félix d’Hérelle, who isolated them in 1917 in the feces of con- existing infrastructure. More precisely here, rather than reinvesting valescing dysentery patients, while he was stationed at the Pasteur the various forms of the antibiotic infrastructure through the prism Institute in Paris (D’Hérelle, 1917). of phages, something that cannot be achieved in a single article, we Though the nature of the bacteriophages was a matter of dis- want to show that antibiotics also form a kind of epistemological pute only resolved in the early 1940s with the invention of the infrastructure, which acts as a powerful inhibitor to the develop- electronic microscope, d’Hérelle made immediate use of his dis- ment of phage therapy. In this sense, we can say that antibiotics covery to treat patients suffering from bacterial infections and actually prevent the development of solutions to the problem they reported great success (Summers, 1993, 2001). During these contribute to create. various studies, d’Hérelle collaborated with George Eliava, who In showing this, we must examine the notion of infrastructure then supervised the creation of a center in Tbilisi in his native as production means. In particular, we will show how regulation Georgia, dedicated to this practice and which was posthumously and innovation are linked through production means, and how given his name (Dublanchet, 2017).

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While phage therapy developed rapidly in Europe and the strain of Acinetobacter baumannii, brought back to the United United States, with phages even being produced by several States in a critical condition, and then treated by phages that cured American pharmaceutical companies, it declined from the 1940s him at University of California San Diego, has given rise to onwards, remaining in these regions within a very confidential numerous articles and a book which enjoys considerable sales context only (For an overview of this period, see Fruciano, 2011). (Strathdee and Patterson, 2019). In England, the case of a cystic However, it has developed significantly in Soviet countries, fibrosis patient with a disseminated drug-resistant Mycobacterium especially Georgia, where it is still widely practiced, as well as in abscessus infection was published in Nature after the patient was Poland and Russia (For a detailed account of the adoption and cured by the use of natural and synthetically modified phages survival of bacteriophage therapy in the USSR, see Myelnikov, (Dedrick et al., 2019). Several trials are underway or will begin in 2018). the coming months, the number of scientificpublicationsonthe The reasons for the decline of phage therapy are complex, and subject has significantly increased, and the various microbiology deserve the full attention of Science historians. However, several conferences held in recent years have given increasing attention to convincing arguments can be put forward at this stage. Firstly, potential therapeutic applications of phages. two reviews on phage therapy published in 1934 (Eaton and This redevelopment of phage therapy may owe much to some Stanhope, 1934) and 1941 (Krueger and Scribner, 1941) in the of its most ardent advocates, but it actually responds above all to a prestigious Journal of the American Medical Association (JAMA), concern that has been growing since the beginning of the 21st reported difficulties in using phages, as well as efficacy problems. century around the appearance of “superbugs”. This is because However, on reading these reviews it becomes obvious that there while phages and certain antibiotics do have a biocidal compe- were still controversies about the mode of action of these viruses tence, their mode of action is fundamentally different.4 at the time. During the same period, the development of sulfo- namides, powerful antibacterial agents, in Germany in the 1930s, and the massive production and use of antibiotics from the 1940s On phages’ mode of action and potential uses onwards in the United States, ran in parallel to the almost While antibiotics are chemical substances, phages are strict parasites complete disappearance of phage therapy in the years that fol- of bacteria, biological entities that have complex and co-evolving lowed. This argument is consistent with the continuation of this relationships with them. Phages can be said to be virulent or practice in some countries of the former USSR, as access to temperate depending on their development cycles: lytic (destruction antibiotics was limited at that time (Kuchment, 2012; Summers, of the bacterial cell by the phage) or lysogenic (insertion of the 2012; Myelnikov, 2018).2 genetic material of the phage into the bacterial DNA, which then Phages, sulfonamides, and antibiotics all seemed to do the gives the bacterium immunity to infection by an identical phage). In same thing: destroy bacteria. Sulfa-drugs, but especially anti- the context of therapeutic use, only virulent phages, i.e. phages that biotics, first and foremost penicillin, just seemed to do it better. can only perform lytic cycles, are therefore relevant. The second half of the 20th century was thus marked by a drastic Figure 1 illustrates the lytic cycle of phages. During the reduction in infectious diseases. It made antibiotics (and sulfa- adsorption phase, the phage attaches itself to the bacterial drugs) one of the greatest achievements in the history of medi- membrane. This step is highly specific; a given phage will gen- cine, and they lastingly influenced the de facto definition of what erally only be able to attach itself to a given bacterial species, and a treatment should be and how it should work. At the same time, sometimes to only some strains (genetic variants) of that species. and partly because of that, phage therapy plunged into almost It then injects its genetic material into the bacterium, which will total oblivion, to the point that at the end of the 20th century, the be replicated via bacterial enzymes, which will also synthesize the hostility toward the use of phages for therapeutic purposes was proteins and lipids needed to form capsides. After assembling the widely shared, a feeling mentioned by all the physicians we met different components to form virions, the bacterium will be lysed, during fieldwork. releasing between 50 and 200 new phages, which can attach In parallel with this massive rejection by part of the infectious themselves to new bacteria and start the cycle over again. disease community, several attempts to develop phage-based In therapeutic use, it is therefore necessary to isolate active biotechnologies took place in the late 1990s and early 2000s, phages against the bacteria responsible for the patient’s infection, whether in human health, animal health, or biocontrol in the amplify them, and administer them in such a way that they come agri-food sector (Hausler, 2006; Kuchment, 2012). Indeed, it is in into contact with the pathogen. In the case of an osteo-articular the latter sector that some initiatives have been successful. Since infection, for example, one of the ways to proceed is to wash the 2007, two anti-Listeria phage cocktails have been approved by the woundwithaphagesolutionbeforeclosingitattheendofsurgery. FDA and the Canadian Environmental Protection Agency (EPA). Phages, multiplying in contact with the host bacteria, will spread as They later also obtained authorization from the European Food long as there are cells left to infect. Once the pathogen is eliminated, Safety Agency (EFSA). In conventional and organic agriculture, the phages, which cannot survive without a host, will then be phages are also used to protect tomato and pepper crops from the degraded. pathogens Xanthomonas pestris and Pseudomonas syringae The mode of action of lytic phages, which is highly specific, (Zaczek et al., 2015). allows for the consideration of the history of infection and the However, the use of phages for therapeutic purposes in human development of a therapeutic approach that takes into account its health never completely disappeared during this period. In France particularities. Phages could thus make it possible (and already do and in Belgium, for example, phage therapy has continued to be so on an ad hoc basis) to treat a number of cases considered critical, used occasionally to treat patients in cases of therapeutic failure which are becoming more and more numerous as part of the (Patay et al., 2019). Over the past 15 years, phage therapy has been gradual establishment of AMR. They could also be an alternative to under development again in laboratories and hospitals. While the antibiotic use, or used together. Some studies show their synergistic results of the first large-scale clinical trial based on a European potential and a reduced acquisition of resistance in bacteria consortium, Phagoburn, are inconclusive (Jault et al., 2019),3 more (Chaudhry et al., 2017). They could be used to decolonize patients and more patients are being treated by phages in France and Bel- before surgery, or to decolonize carriers of Staphylococcus aureus gium (Jennes et al., 2017; Ferry, Boucher et al., 2018,Ferry, working with immune-depressed patients (Narasimhaiah, 2013). Leboucher et al., 2018;Djebaraetal.,2019). In the United States, the The specificity of phages makes it possible to target only the case of Tom Patterson, who was infected in Egypt by a toti-resistant pathogen responsible for the infection to be treated, and thus to

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second approach, especially since requests from both patients and physicians continue to increase. The Belgian government, in partnership with a research team from the Queen Astrid Military Hospital, has even modified its regulations since 2017 (Pirnay et al., 2018), a point to which we will return below. Whether in the literature of or in the various interviews con- ducted over the past 2 years, the issue of regulation appears to be central. Until the early 2000s, the term “bacteriophages” did not appear in any regulatory text. In recent years there has been a desire to regulate practices. However, the way they are captured in the texts leads to a preference for the ‘prêt-à-porter’ model. In the rest of this article, we will describe the concrete consequences of this regulatory capture for the development of this therapy and its potential role in the fight against AMR.

The regulatory framework: phages as industrial medicinal products There is no specific regulation around phages. Since 2011, phages have been considered as a drug in the United States (Fauconnier, 2019) or a medicinal product in the European Union5: a sub- stance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immuno- logical or metabolic action”,asdefined on the European Medi- cines Agency (EMA) website.6 As mentioned in Volume 1 of Rules Governing Medicinal Products in the EU, “Today the EU legal framework for medicinal products for human use guarantees high standards of quality and safety of medicinal products, while Fig. 1 The phage replication cycle. This figure is not covered by the promoting the good functioning of the internal market with 7 Creative Commons Attribution 4.0 International License. Reprinted by measures that encourage innovation and competitiveness.” permission from Springer Nature: Nature Reviews Microbiology, This qualification of phages as a medicinal product for human Bacteriophage Resistance Mechanisms, Simon J. Labrie et al. (2010), all use was endorsed on June 8, 2015 at an EMA workshop, even rights reserved. though those present at the event who were all working on phage development (doctors, microbiologists, pharmacists, specialists in phage–bacteria interactions), warned that such categorization was preserve the commensal or mutualist bacteria that compose the inadequate. Following this meeting, they expressed their opposi- microbiota, whose role in human health we are only just begin- tion in a short two-page letter, mentioning two aspects in parti- ning to understand. But this potentiality offered by phages cular: (i) the need to create a new regulatory framework, which depends in part on the type of approach favored in the devel- would (ii) counterbalance the lack of public and private invest- opment models of the therapy (a point to which we will return ment in phages (Debarbieux et al., 2015). more precisely in our conclusion). In order to better understand their position, let us return In an article published in 2011, following the First Interna- briefly to the categorization of phages as medicinal products as tional Congress on Viruses of Microbes held from June 21 to 25, per the European Directive 2001/83/EC. It applies “to medicinal 2010 at the Pasteur Institute in Paris, the 19 authors, who are all products for human use intended to be placed on the market in phage specialists, contrasted two approaches: “prêt-à-porter” and Member States and either prepared industrially or manu- “sur-mesure”. The ‘prêt-à-porter’ approach can be understood as factured by a method involving an industrial process” (Fau- the production of fixed cocktails: several phages (it can be about connier, 2019, p. 2). For ease of writing, we will refer to them as 10) are put together in order to have at least one that will be ‘industrial medicinal products’ in the following sections. This effective on the strain carried by the patient to whom the cocktail applies to the member countries of the European Union but will be administered. This approach allows for standardized also to the United States, since both are members, along with commercial products. “Sur-mesure” describes an approach where Japan, of the International Conference on Harmonization of patients will only be administered the few phages that are actually Technical Requirements for Registration of Pharmaceuticals for active on the strain responsible for their infection. In just a few Human Use (ICH) created in 1990. The ICH’s objective is to paragraphs, the authors combine AMR, regulation, microbial create a global market through the harmonization of regulatory evolution, drug market, technical problems, fundamental requirements relating to the quality, safety, and efficacy of research, pharmaceutical companies, hospitals, intellectual prop- medicines by implementing the principles of reciprocity and erty, sewage and scientific evidence, to name but a few, all mutual recognition between the three reference regulatory necessary to understand the relevance and wisdom of the oppo- authorities of the United States, Japan, and the European sition between these two approaches. While they argue that the Union.8 Therefore, rules and guidelines that apply in Europe two can coexist, the authors’ wish is to see the development of the also apply in the United-States and more broadly, as they have “sur-mesure” approach, which they believe takes into greater become international standards. account the particularities of phages and their interactions with This has three major consequences: (i) phages must be pro- bacteria (Fig. 2). duced according to good manufacturing practices (GMPs), a set Since the publication of this article, discussions have been of strict standards and procedures to ensure the quality of the initiated at the European level to try to give substance to this finished product; (ii) phages must demonstrate their efficacy and

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Fig. 2 Phage therapy concepts, ‘prêt-à-porter’ vs. ‘Sur-mesure’. This figure is not covered by the Creative Commons Attribution 4.0 International License. Reprinted by permission from Springer Nature: Pharmaceutical Research, The Phage Therapy Paradigm: Prêt-à-porter or Sur-mesure? Jean-Paul Pirnay et al. (2011), all rights reserved. safety in RCTs (Phase I, II, III, and IV); (iii) phages must obtain In the United States, patients can be treated by phages fol- marketing authorization. Research and development on phages is lowing the emergency investigational new drug (eIND) pathway thus placed within the framework of an industrially based drug of the FDA (expanded access program).10 In France, the ANSM economy. has opted for an accompaniment of compassionate uses in the This is the case in France, where phages must be prepared form of a Temporary Use Authorization, which normally applies industrially by pharmaceutical establishments according to to products under evaluation or about to obtain a marketing GMPs.9 GMPs are part of the quality assurance system put in authorization. Although the phages available in the country, and place by the pharmaceutical industry to ensure the production of in the European Union more generally, do not yet meet these medicines in a systematic, standardized, and controlled manner requirements, there are phages still in the prototype stage (pro- according to the quality standards appropriate to their use, and in duced by research laboratories) which are not manufactured compliance with the granting of marketing authorization by the according to GMP standards, that the ANSM regularly supports national regulatory authorities (Brhlikova et al., 2007). In France, for several patient treatments, thus demonstrating its commit- the marketing authorization is delivered by the French National ment to promoting this therapy.11 ANSM after evaluating the dossier submitted by the pharma- From the cases that we have observed or documented or that ceutical industry. It must include the results of clinical trials have been reported to us during interviews, a patient’s treatment demonstrating efficacy and elements regarding the benefit/risk plan can be summarized as follows: after discussion and valida- ratio. Currently there is no marketing authorization for phages in tion with the ANSM and a committee of experts on the appro- France, the European Union, or the US. priateness of the use of phages in the treated infection, the While they cannot fulfill these different obligations, phages are infectiologist or physician in charge of the patient takes a bacterial generally used in the context of Article 37 of the Helsinki sample, isolates the pathogenic strain and sends it to one of the Declaration (for a detailed inventory of the different regulations laboratories likely to have one or more active phages. The latter in the European Union countries, see Pirnay et al., 2019). performs a phagogram, i.e. s/he tests the activity of the different

PALGRAVE COMMUNICATIONS | (2020) 6:100 | https://doi.org/10.1057/s41599-020-0478-4 | www.nature.com/palcomms 5 ARTICLE PALGRAVE COMMUNICATIONS | https://doi.org/10.1057/s41599-020-0478-4 phages available to her/him on the bacterial strain. If one or more Surviving start-ups established in the 2000s therefore generally phages are active, they will then be produced and purified and work on only a few specific phages of a few bacteria, most often sent to the pharmacist and physician for administration. Staphylococcus aureus or Pseudomonas aeruginosa, responsible It appears that the main limiting factor today is the number of for the most commonly encountered antibiotic-resistant infec- phages available to doctors, which might seem counter-intuitive tions, but also more rarely and more recently Escherichia coli. given that phages are the most abundant biological entity on The categorization of phages as an industrial medicinal pro- Earth. The high specificity of phages for bacteria implies the need duct thus leads to a discrepancy between the need to have large to have a wide enough diversity of phages available to be able to collections of phages available (even if not all the different find one or more that are likely to be effective in treating the interlocutors hold the same view on the number of phages needed infection of a given patient. When a bacterial strain is sent to or the degree of specificity—questions that we do not address laboratories likely to have active phages, the phagogram is most here because they are not necessary at this stage), and production often negative. One of the doctors we met sent a bacterial strain to standards, which are designed within the framework of the seven different laboratories all over Europe to find an active commodification of health products, and which make it very phage. These were research laboratories, rather than pharma- difficult (in terms of financial, human, and technical means) to ceutical companies or start-ups. Another frequent occurrence is obtain a large number of phages manufactured in compliance that in the absence of active phages within available collections, with GMPs. research laboratories engage in phage hunting, searching for new This is one of the reasons why the Belgian Government, under phages in the rich waters of the surroundings (waste water, the impetus of a team of researchers from the Queen Astrid sewers, treatment plants), before producing and sending them. Military Hospital in Brussels, decided in 2017 to no longer con- This scheme is beset with problems, which manifest themselves as sider phages as industrial medicinal products but as Active Pro- many scientific and technical steps and challenges in the devel- duct Ingredients in magistral preparations (APIs). This move has opment of phage therapy. However, some are more significant allowed the Belgian hospital to manufacture phages for treatment. than others, and are directly related to the categorization of However, there are still points that need to be clarified, as there is phages as industrial medicinal products. no clear consensus on the requirements and standards for API The practices described above are only tolerated. While the production. For some people we met, APIs must meet the same ANSM, for example, supports doctors who want to treat patients standards as medicinal products. This once again reveals the with phages produced by research laboratories (phages that difficulties encountered by all actors around the understanding of obviously meet strict specifications in order to prevent any toxi- the regulatory texts and the possibility of including phage therapy city), the fact remains that, in line with European regulations that in them. make phages medicinal products, the agency favors phages pro- From this point of view, classification as an API does not solve duced according to GMP standards, i.e. industrial phages. the issues and difficulties of production. To this we must add that Here, the materiality of phages and their coevolutionary although this shift may facilitate access to therapy for individual capacities with bacteria come into play. Phages are dynamic patients, it does not, however, allow the realization of RCTs, entities that evolve very quickly. One of the problems faced by which are conditioned on the use of phages produced according phage producers is then to ensure the stability of their product, a to GMP standards. Yet RCTs are absolutely necessary for the difficult task as phages are produced using bacteria. Conse- development of phage therapy, even if, as we will see, the quently, producers must not only isolate, characterize, and purify administration logistics of the evidence of phage efficacy via RCTs phages, but they also have to stabilize them to prevent them from is problematic to say the least. mutating. Another problem faced by producers is cross-con- tamination, since phages are able to interact with non-targeted bacteria. This is a well-known problem in dairy industry, where Categorizing anti-infectives: phages as an umpteenth phages are considered a nuisance, as they can destroy the bacteria antibiotic needed for fermentation processes. This therefore implies the In the problems frequently raised by the various actors involved, construction of dedicated production units, including clean whether doctors, researchers, pharmacists, or regulators, the dif- rooms, where the particle concentration is controlled in order to ficulty of producing evidence of phage efficacy occupies an limit the risks of contamination, as well as the required tem- important place. Although everyone may agree on their necessity perature, humidity, and pressure levels. These kinds of facilities to demonstrate the safety and efficacy of phages, RCTs, the gold are very costly. standard of Evidence-Based Medicine, are considered as another In addition, it should be noted that producers face ownership obstacle to the development of phage therapy. Indeed, at this problems. Currently, as a Belgian physician told us, the only time, the only conclusive trial on phage therapy relates to the ownership protection available is in the form of ‘gentleman’s treatment of chronic otitis (Wright et al., 2009). The argument agreements’. This is untenable for start-up actors we’ve met, who most frequently used in interviews, but also in scientific articles, are actively searching for solutions to protect their work. Indeed, concerns the strong specificity of phages. unlike chemical molecules that can be quite easily patented, While the failure of the first major trial in Europe, Phagoburn, phages are natural entities, and are currently not patentable highlighted some technical problems (Jault et al., 2019), several (whether in North America or Europe). Different strategies are articles published by proponents of phage therapy in Europe evoked in interviews or in published papers: processes (of pro- during the last few years focus on two main elements: (i) the duction, of purification) could be patented; or ‘trade secrets’ inadequacy of clinical trials to demonstrate the efficacy of phages model could be followed, where, like for the Coca-Cola recipe, a because of their specificity and therefore the personalized nature company would not disclose their know-how, in order for some of the treatment (Pirnay et al., 2019); and (ii) the major difference start-ups to maintain their advantage over potential competitors between what is evaluated in trials and what occurs in real life (Todd, 2019). This contributes to the difficulties for start-ups to (Patay et al., 2019). find and keep investors, and can also explain, along with Big These two types of arguments, albeit crucial, are not specificto Pharma disengagement from the field of anti-infective drugs, why phages. Out of all the interviews conducted, in this section, we pharmaceutical firms are not committed to the development of mainly focus on comments from two physicians, both of whom phage therapy. are actively working on the development of clinical trials in

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France. Their roles are which is representative of the positions indicated for treatment of bacterial infections (European Medi- held by all of the interviewees: a doctor who has spent her entire cines Agency, 2019), whose aim is to “facilitate clinical career in Big Pharma, who was in charge of an anti-infective development programs for new antibacterial agents (…)to drugs department, and is now working on phage development in ensure that each clinical trial conducted can be designed to meet a start-up; and a French physician, head of an infectious diseases the requirements of multiple regulatory agencies” (European department in a public hospital which regularly uses phages. Medicines Agency, 2019, p. 4). While previous versions of this Thus, in an interview about the pitfalls of clinical trials, the guideline never mentioned phages, this one states that principles doctor working in the start-up dismissed specificity as a valid reason covered in this guideline are also applicable to their development to explain the difficulties in the development of this therapy: (European Medicines Agency, 2019, p. 5), a point emphasized by the physician later in the same interview: “I am however less concerned about specificity. Antibiotics and bacteria may not evolve together and they’re not two “It means that the pathway might not be the same, but in living entities (…), but antibiotics also target very specific any case we must stick as closely as possible to the existing bacteria. So I’m not hugely convinced about the idea of guidelines for antibiotics.” specificity.” (June 2019). Indeed, personalized therapies are evaluated by RCTs on a (June 2019). daily basis. In the field of infectious diseases more specifically, the These new guidelines imply that the efficacy of phages must be antibiotics developed over the past 20 years are themselves very proven on the same basis as that of any antibiotic. The problem is specific, which has not prevented them from proving their effi- that due to ethical standards, which state that patients must cacy. Regarding the difference between clinical trials and real life, always be given the best available treatment, phages are system- the existing literature clearly demonstrates that this problem is atically used with antibiotics. This has a major consequence for not specific to phages, but concerns all trials, except phase IV the design of RCTs. The public hospital infectiologist says: trials, which are set up precisely to close this gap (Brives et al., “ fi ’ 2016; Adams, 2016; Brives, 2018). This is not to say that these two For incontestable scienti c proof, we d need to conduct a therapeutic trial; a therapeutic trial with hundreds of problems are not important, only that, as they arise for all + treatments, they alone cannot explain the obstacles to the patients who are randomly selected for surgery antibiotic development of phage therapy. While the specificity of phages is treatment versus, and this is where it get more complicated, other patients with the same infection who receive surgery central in the understanding of the barriers imposed by current + + ” regulations, particularly regarding production issues, it is only antibiotics phages. one problem among many which help to illustrate the difficulties faced by physicians and researchers in assessing the efficacy of (April 2019). phages. So, what makes it so difficult to produce evidence in the And indeed, the design of the different trials, conducted, about to case of phage therapy? start, or under development, systematically contrasts a control arm using antibiotics and an intervention arm using phages + antibiotics. What is tested is therefore not one anti-infective against Phages as an umpteenth antibiotic. It was through discussion another, but only the increase in efficacy associated with the with physicians, epidemiologists, and funders, and analysis of the addition of phages to antibiotics. This poses two challenges: (i) design of clinical trials, both those already carried out and the one due to the specificity of phages towards a given bacterium, all we are currently involved in, that another hypothesis emerged. recruited patients must be infected with the same bacterium, or Indeed, in most of the interviews conducted on evidentiary even with only certain strains of this bacterium (those sensitive to practices with physicians, epidemiologists, and regulators, we phages); (ii) since antibiotics are still quite effective, except in the found that phages were considered as another type of antibiotic. case of toti-resistant bacteria, the number of patients that would Thus, as mentioned by the French physician working in the need to be included to statistically show a significant increase in public hospital: efficacy is colossal. “ We are faced here with a problem: if AMR is indeed increasing, Phages are one solution among others, because there are and is certainly already a problem, it is above all a problem in the lots of interesting ideas coming out. There are new anti- fi making; for the time being antibiotics retain a large part of their bio lm antibiotics, antibodies coupled with antibiotics efficacy, which makes it extremely difficult, time-consuming and which deliver the antibiotic to the inside of cells, and there fi fi ” costly to demonstrate the ef cacy of phages according to current are speci c anti-infective gels which can carry antibiotics. EBM standards. (April 2019). Eradication or containment, or how to use phages and anti- This assimilation is even more clearly reflected in the biotics. Another problem with the assimilation of phages to comments of the physician working in the start-up: antibiotics in RCTs concerns the efficacy criterion chosen. With “I see it more in terms of a toolbox: what tools do I have as regard to the protocols and discussions conducted with clinical trial investigators, the most robust efficacy criterion for an anti- an infectiologist when I’m faced with an infection, and what do I use to treat that infection. Phage therapy is one of infective drug is the eradication of the pathogenic bacterium, as the start-up doctor, who is currently working specifically on the those tools, but I see it as pretty much the umpteenth antibiotic (…) That’s how I see it. It’s an additional tool you criteria issue pointed out: can use to treat the patient.” “A robust efficacy criterion for an anti-infectious product is usually to show that the infection no longer exists, that the (June 2019). bacteria is no longer present.” This interpretation has recently been reinforced by the latest guideline concerning the Evaluation of medicinal products (February 2019).

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However, the current use of phages in therapy makes this guidelines, recommendations, and regulations on anti-infective criterion particularly difficult to document. For example, two products. trials are about to begin, one on prosthetic Staphylococcus aureus Although these divergences make it very difficult, time- infections and the other on foot ulcer infections in diabetic consuming and costly to prove the efficacy of phages via clinical patients. In both cases, once the wounds have healed, it becomes trials designed according to current guidelines and regulations, it very difficult to document the eradication of the bacterium. If this is not impossible. But according to the various actors we met, it is not an issue in itself for these phase II trials, which are not will demand adjustments and negotiations, a point highlighted by intended to prove the efficacy of phages but their absence of the start-up doctor’s comments after one and a half hours of toxicity, it is a concern for phase III trials, as several physicians discussion on efficacy and cure criteria: have pointed out in the various interviews conducted. “ ’ fi Eradication as a criterion of efficacy also raises questions about I m the rst to say that the dogma of antibiotics has a hold the relevance of definitions of cure in the context of infectious over me. There are guidelines and we must follow them as fi closely as possible, or it won’t be accepted. (…)Proof of diseases. While eradication is perfectly justi ed in some cases, fi ’ particularly in the treatment of acute infections, several doctors ef cacy will always be required. If today s blueprint is no are more measured for chronic infections, for which phages longer valid, what blueprint do we follow? What is acceptable? I don’t have the answer and I can’t find it would be particularly suitable. Thus, an intensive care physician … at a major Parisian hospital, who is also doing a Biological Science alone ( ). Perhaps we need to completely reinvent history, the whole history of proof of efficacy. And we’re not going Ph.D. thesis on phages, explained to me that in the case of ” chronic infections, it was not so much the eradication of the to do it alone. bacterium, but rather the restoration of a better functional status of the patient that was targeted: (June 2019). “ ’ In all the interviews we conducted, all the actors (regulators, I think we ll continue to use antibiotics for probabilistic, doctors, pharmacists, researchers, investors) agreed on the need empirical circumstances. For example, when you come to to produce reliable data via RCTs. While there is a consensus on hospital with pyelonephritis, there’s no time, we don’t know ’ this point, potential solutions have yet to be found. Phages are who you are, and we treat you with medicine because it san biotherapies, in the same way as maggots, larvae, helminths emergency. But I believe phages have a place in the ’ (Grassberger et al., 2013), and more recently the fecal microbiota treatment of more chronic infections. I think it s a problem transplant (FMT) to treat Clostridium difficile infections. As that antibiotics are constantly trying to eradicate things: such, it might be interesting to look at how these therapies have niches that are actually favorable to strains. And the ’ been evaluated in the framework of RCTs. However, if in these problem is if you eradicate something that wasn t actually different cases, living dynamic entities are used in human therapy, all that bad, you don’t know what it might be replaced ” an additional constraint is placed on the therapy in question. As with. we have already mentioned, phages are not only highly specific, which makes them similar to personalized medicine (for which (November 2018). specific designs exist, such as the n-of-1 trial, designed for one This argument was also mentioned by a cystic fibrosis specialist patient), but also very unstable due to their evolvability. This is who reminded us during a workshop that his aim was not to not to say that RCT is totally unsuited to this therapy, but rather eradicate a multi-resistant lung infection, but rather to maintain it that the problems it faces, which are both regulatory and at a tolerable level for his patient.12 This approach was also epistemological, can only be resolved through collegial and highly favored by an infectiologist working on complex osteo-articular interdisciplinary discussions. infections, who recalled during an interview the multiple definitions attributed to healing, and the choices that were made according to the patient. If the microbiological definition of Conclusion/discussion healing is indeed the eradication of infection, which may for According to the various stakeholders met, and in view of the example require the amputation of a limb, the orthopedic increasing number of documented cases available, phage therapy definition will be the preservation of that limb by maintaining an appears to be a promising alternative in the treatment of certain 13 infection at a threshold acceptable to the patient. bacterial infections, multi-resistant or not. Due to the lack of data These statements, which reflect an ecological and holistic vision from RCTs, phages are currently only used in complex cases for of the disease, made up of interspecific population dynamics, do patients in therapeutic failure, and are always accompanied by not reject eradicationism. They only make it a possibility of action antibiotic treatment. However, the possibilities of application are among others in achieving healing according to the patient’s multiple, and it is entirely conceivable that they could in some biographical context. Thus, the distinction between acute and cases be used instead of antibiotics. Thus, they potentially have chronic infection is fundamental, as is the distinction made by the the power to control some existing superbugs, while limiting the intensive care physician between phages and antibiotics. Two emergence of new ones, by limiting the use of antibiotics. The substances, two different entities, which, because of their potential applications go well beyond human health, being differences, will not be used to achieve the same objectives. applicable also to biocontrol, animal health and the environment By highlighting the range of relationships we have with (Mahony et al., 2011; Chan and Abedon, 2015; Buttimer et al., microbes, by showing that infection can be tolerated if it allows 2017; Fernandez et al., 2018). the maintenance of a good functional status for the patient or if it But phages, dynamic and evolutionary entities, are, as we have prevents a more virulent and difficult-to-treat pathogen from shown, framed, classified, categorized, as chemical molecules. In occupying the environment, by pointing out that mediating furthering Chandler’s line of thought, we therefore wished to entities do not have the same agencies, these researchers reveal a show that we can think of antibiotics as an epistemological clear discrepancy between what happens in infection manage- infrastructure that constitute an obstacle to the development of ment practices (with or without phages, antibiotics for example phage therapy, imposing constraints, and conceptions of treat- being able to act as mediators of pathogen virulence as well) and ment and cure, eradicationism being the baseline. Once again,

8 PALGRAVE COMMUNICATIONS | (2020) 6:100 | https://doi.org/10.1057/s41599-020-0478-4 | www.nature.com/palcomms PALGRAVE COMMUNICATIONS | https://doi.org/10.1057/s41599-020-0478-4 ARTICLE there is no question of denying the importance of RCTs, only of are not exclusively based on eradication; if we remain cautious showing the issues and assumptions around their design. about the appearance of a probiotic turn (Lorimer, 2017), phages, However, it seems important to us to conclude on the different by their very nature, their plasticity and their omnipresence, conceptions of life mobilized in biomedicine and, beyond that, in constitute a wonderful case study for rethinking our relationships the choices of development models and public health policies. with non-human living beings, and documenting and analyzing In an article on AMR, Hannah Landecker highlights how the the way we construct these relationships, as well as the material development, followed by the production and mass consumption consequences of these enactments. These models can also take of antibiotics, has contributed to changing the very biology of into account the ever-increasing inequalities in access to care, in a bacteria. “The bacteria of today are not the bacteria of yesterday, context of austerity that affects both the Global South and the whether that change is registered culturally, genetically, physio- countries of the North; because economic actors face problems of logically, ecologically or medically” (Landecker, 2016, p. 3). In the privative appropriation, and because phages are not entirely history of antibiotic treatment, what has not been sufficiently scalable, in the sense developed by Tsing (2015), it is possible to taken into account, despite early warnings from scientists and envision an exit from a capitalist model of production. doctors (Gradmann, 2017), are the formidable adaptive capacities It is now a question of taking note of these differences, and of bacteria, and of living organisms in general. What has been therefore slowing down, to follow Isabelle Stengers’ suggestion denied is the ability of the living to act and react. Phages, through (2018) to take the time to design new ways of interacting with their long co-evolutionary history with bacteria, are a valuable microbes, and new paths to think of medicine and care. In this resource. Therefore, their assimilation to other ranges of anti- sense, the various bottlenecks identified in this article based on infectives, which are chemical molecules and not biological the data presented can be interpreted as many entry points, as entities, results from a reification of living organisms, which many opportunities, to imagine possible futures, “material futures considerably reduces the consideration of their agency. This could [that are not] produced by what we thought we knew” (Land- then be problematic, with regards to both the modalities of their ecker, 2016, p. 19). use and the consequences of these. By assimilating phages to industrial medicinal products, the Data availability current regulations thus impose a de facto commodification of The original data generated during and/or analyzed during the living organisms, and a form of forced scalability, to which, as we current study are not publicly available as individual privacy have seen, phages are difficult to mold. But the difficulties raised could be compromised but are available from the corresponding by this commodification are not insurmountable. With time, author on reasonable request. determination and financial resources, start-ups and/or pharma- ‘ ’ ceutical companies will eventually market prêt-à-porter cocktails Received: 19 December 2019; Accepted: 22 April 2020; that will aim to eradicate several different bacteria. And then the assimilation of phages to antibiotics will take place, giving phy- sicians a ‘product’ that will only partially correspond to the expectations and practices of the infectiologists and doctors we met, who maintain a rather more ecological and dynamic con- Notes ception of infection.14 1 Interviews lasted between 1.5 and 3 h. They took place face-to-face and were We can identify two potential problems here. Firstly, nobody recorded, transcribed, and anonymized. today is able to predict the effect of mass use of phage cocktails, 2 We do not elaborate here on the considerable importance of bacteriophages for the all the more so if their use in animal health or biocontrol were to development of molecular biology, since exchanges between fundamental research become more widespread. The data accumulated over the last 20 and therapeutic applications have been, in view of current research, almost non- years or so on microbiotes, and well before that on microbial existent. (For a history of these viruses and their role in the production of scientific ecosystems, lead to a certain humility concerning the potential knowledge, see Kay 1993, Morange 1998.) We also leave to one side phage-typing, a method used for detecting single strains of bacteria, and a powerful tool of 20th- applications of this new knowledge offered by Science. We no century epidemiology (Kirchhelle, 2019). longer have the luxury today of being able to disconnect the use 3 For complex reasons related less to the effectiveness of phages than to the actual of phages in human and non-human contexts. design of the clinical trial protocol and the choice of infections to be treated. Secondly, the price of phage treatment is likely to be very high. 4 Not all antibiotics are biocidal. Some act by preventing bacterial multiplication. The abandonment by Big Pharma of the development of antibiotics 5 Directive 2001/83/EC of the European Parliament and the Council on the for economic and financial reasons in favor of much more profit- Community code relating to medicinal products for human use. 6 https://www.ema.europa.eu/en/glossary/medicinal-product (consulted on August able drugs to treat chronic conditions (Green, 2007)hasledtothe 20, 2019). arrival of a large number of start-ups and small companies. This 7 https://ec.europa.eu/health/human-use/legal-framework_en (consulted on August situation is similar for the production of phages, which depends on 20, 2019). the commitment of start-ups and the goodwill of shareholders and 8 However, no association of generic manufacturers and no regulatory authority from investors. In the case of phage therapy, start-ups could be supported “Southern” countries participate in ICH. The WHO has only one observer seat but no by not-for-profit R&D organizations, such as CARB-X in the voting rights (Hauray, 2006). 9 As per Article L. 511-1 of the French Public Health Code. United States or GARDP in Switzerland, created recently for the 10 https://www.fda.gov/drugs/investigational-new-drug-ind-application/emergency- development of new antibacterial treatments. However, as far as we investigational-new-drug-eind-applications-antiviral-products (accessed on 4 know, these organizations have so far favored chemicals. This March 2020). development model, based on start-ups, implies access will be to a 11 In the US, some patients are treated with phages following the emergency very limited part of the world population, when we know that AMR investigational new drugs (eNID) pathway of the FDA (for more details see problems will primarily impact the Global South. Fauconnier, 2019). fi 12 Personal communication, 21 March 2019. Denying the speci cities and temporalities of microorganisms, 13 interview conducted on 26 April 2019. and commodifying them poses significant risks. Other models, 14 This conception is not knew: an “ecological vision in biomedical science” can be which could produce phages at a lower cost, and enable a case-by- found in the work of scientists like Theobald Smith, F. MacFarlane Burnett, René case approach are possible. These models can take into account Dubos, or Frank Fenner, which remained of minimal interest until the 1980s, when it the specificities of phages and their relationship to bacteria, and was used to explain disease emergence and antibiotic resistance (Anderson, 2004).

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Acknowledgements Open Access This article is licensed under a Creative Commons We are grateful to everyone who agreed to meet and participate in our survey. We thank Attribution 4.0 International License, which permits use, sharing, all the members of the different scientific networks on phage therapy for their reflections adaptation, distribution and reproduction in any medium or format, as long as you give and for the enriching discussions that helped in the writing of this paper. All inter- pretations and inaccuracies remain the responsability of the authors. This work was appropriate credit to the original author(s) and the source, provide a link to the Creative funded in part by the support of the Agence Nationale de la Recherche (ANR) [Grant Commons license, and indicate if changes were made. The images or other third party ’ number ANR-18-CE36-0001] and the New-Aquitaine region [Grant number 2018- material in this article are included in the article s Creative Commons license, unless 1R40218]. indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from Competing interests the copyright holder. To view a copy of this license, visit http://creativecommons.org/ The authors declare no competing interests. licenses/by/4.0/.

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